Characterization of a selective, iron-chelating antifungal compound that disrupts fungal metabolism and synergizes with fluconazole

• DOI: 10.1128/spectrum.02594-23
• Publication Date: 2024-01-17T14:00:44Z
• Authors: Jeanne Corrales; Lucia Ramos-Alonso; Javier González-S...; Nicolás Ríos-Lomb...; Nuria Trevijano-C...; Henriette Engen Berg; Frøydis Sved Skot...; Francisco Moris; Oscar Zaragoza; Pierre Chymkowitch; Ignacio Garcia; Jorrit M. Enserink
• Keywords: Galleria mellonella; Candida glabrata; Antifungal drugs; Echinocandins

ABSTRACT Fungal infections are a growing global health concern due to the limited number of available antifungal therapies as well emergence fungi that resistant first-line antimicrobials, particularly azoles and echinocandins. Development novel, selective is challenging similarities between fungal mammalian cells. An attractive source potential treatments provided by ecological niches co-inhabited bacteria, fungi, multicellular organisms, where complex relationships multiple organisms have resulted in evolution wide variety antimicrobials. Here, we characterized several analogs one such natural compound, collismycin A. We show NR-6226C has activity against pathogenic Candida species, including C. albicans glabrata , whereas it only little toxicity Mechanistically, selectively chelates iron, which limiting factor for during infection. As result, treatment causes severe mitochondrial dysfunction, leading formation reactive oxygen metabolic reprogramming, reduction ATP levels. Using an vivo model infections, significantly increases survival -infected Galleria mellonella larvae. Finally, our data indicate synergizes strongly with fluconazole inhibition . Taken together, promising compound acts chelating iron disrupting functions. IMPORTANCE Drug-resistant emerging threat, pan-resistance current increasing problem. Clearly, there need new drugs. In this study, novel agent, analog NR-6226C. favorable profile human cells, essential further clinical development. unraveled mechanism action found disrupts homeostasis thereby depletes cells energy. Importantly, potentiates fluconazole, providing inroads combination therapy may reduce or prevent azole resistance. Thus, development into treatment.